Candan Plus is indicated for the:
• Treatment of essential hypertension in adult patients whose blood pressure is not
optimally controlled with candesartan cilexetil or hydrochlorothiazide monotherapy.

The recommended dose of Candan Plus is one tablet once daily.
Dose titration with the individual components (candesartan cilexetil and hydrochlorothiazide) is
recommended. When clinically appropriate a direct change from monotherapy to Candan Plusmay be
considered. Dose titration of candesartan cilexetil is recommended when switching from
hydrochlorothiazide monotherapy. Candan Plusmay be administered in patients whose blood pressure
is not optimally controlled with candesartan cilexetil or hydrochlorothiazide monotherapy or Candan
Plus at lower doses.
Most of the antihypertensive effect is usually attained within 4 weeks of initiation of treatment.

Candan plus should not be administered with aliskiren in patients with diabetes mellitus or renal impairment. Hypersensitivity to the active substances or to any of the excipients or to sulfonamide derived active substances. Hydrochlorothiazide is a sulfonamide derived active substance. Pregnancy, since there is no experience with the use of Candan Plus in pregnant woman, Candan Plus should not be used in pregnancy (see warnings, pregnancy and lactation) Severe renal impairment (creatinine clearance < 30 ml/min/1.73 m2 BSA). Severe hepatic impairment and/or cholestasis. Refractory hypokalaemia and hypercalcaemia. Gout.

Dual blockade of the renin-angiotensin-aldosterone system (RAAS).
Combination therapy of ACEI and ARB drugs may cause an increased risk of hyperkalemia,worsening
of the kidney function and hypotension.therefore,this combination should not be used especially in
patients with kidney problems.
Renal impairment /kidney transplantation
Loop diuretics are preferred to thiazides in this population. When Candan Plus is used in patients with
impaired renal function, a periodic monitoring of potassium, creatinine and uric acid levels is
recommended.
There is no experience regarding the administration of Candan Plus in patients with a recent kidney
transplantation.
Renal artery stenosis
Medicinal products that affect the renin-angiotensin-aldosterone system, including angiotensin II
receptor antagonists (AIIRAs), may increase blood urea and serum creatinine in patients with bilateral
renal artery stenosis or stenosis of the artery to a solitary kidney.
Intravascular volume depletion
In patients with intravascular volume and/or sodium depletion symptomatic hypotension may occur, as
described for other agents acting on the renin-angiotensin-aldosterone system. Therefore, the use of
Candan Plus is not recommended until this condition has been corrected.
Anaesthesia and surgery
Hypotension may occur during anaesthesia and surgery in patients treated with angiotensin II
antagonists due to blockade of the renin-angiotensin system. Very rarely, hypotension may be severe
such that it may warrant the use of intravenous fluids and/or vasopressors.
Hepatic impairment
Thiazides should be used with caution in patients with impaired hepatic function or progressive liver
disease, since minor alterations of fluid and electrolyte balance may precipitate hepatic coma. There is
no clinical experience with Candan Plus in patients with hepatic impairment.

Aortic and mitral valve stenosis (obstructive hypertrophic cardiomyopathy)
As with other vasodilators, special caution is indicated in patients suffering from haemodynamically
relevant aortic or mitral valve stenosis, or obstructive hypertrophic cardiomyopathy.
Primary hyperaldosteronism
Patients with primary hyperaldosteronism will not generally respond to antihypertensive medicinal
products acting through inhibition of the renin-angiotensin-aldosterone system. Therefore, the use of
Candan Plus is not recommended in this population.
Electrolyte imbalance
Periodic determination of serum electrolytes should be performed at appropriate intervals. Thiazides,
including hydrochlorothiazide, can cause fluid or electrolyte imbalance (hypercalcaemia, hypokalaemia,
hyponatraemia, hypomagnesaemia and hypochloraemic alkalosis).
Thiazide diuretics may decrease the urinary calcium excretion and may cause intermittent and slightly
increased serum calcium concentrations. Marked hypercalcaemia may be a sign of hidden
hyperparathyroidism. Thiazides should be discontinued before carrying out tests for parathyroid
function.
Hydrochlorothiazide dose-dependently increases urinary potassium excretion which may result in
hypokalaemia. This effect of hydrochlorothiazide seems to be less evident when combined with
candesartan cilexetil. The risk for hypokalaemia may be increased in patients with cirrhosis of the liver,
in patients experiencing brisk diuresis, in patients with an inadequate oral intake of electrolytes and in
patients receiving concomitant therapy with corticosteroids or adrenocorticotropic hormone (ACTH).
Treatment with candesartan cilexetil may cause hyperkalaemia, especially in the presence of heart
failure and/or renal impairment. Concomitant use of Candan Plus and potassium-sparing diuretics,
potassium supplements or salt substitutes or other medicinal products that may increase serum
potassium levels (e.g. heparin sodium) may lead to increases in serum potassium. Monitoring of
potassium should be undertaken as appropriate.
Thiazides have been shown to increase the urinary excretion of magnesium, which may result in
hypomagnesaemia.

Metabolic and endocrine effects
Treatment with a thiazide diuretic may impair glucose tolerance. Dose adjustment of antidiabetic
medicinal products, including insulin, may be required. Latent diabetes mellitus may become manifest
during thiazide therapy. Increases in cholesterol and triglyceride levels have been associated with
thiazide diuretic therapy. At the doses contained in Candan Plus, only minimal effects were observed.
Thiazide diuretics increase serum uric acid concentration and may precipitate gout in susceptible
patients.

Photosensitivity
Cases of photosensitivity reactions have been reported during use of thiazide diuretics (see
Undesirable effects). If a photosensitivity reaction occurs, it is recommended to stop treatment. If readministration
of treatment is essential, it is recommended to protect areas exposed to the sun or to
artificial UVA radiation.
General
In patients whose vascular tone and renal function depend predominantly on the activity of the reninangiotensin-
aldosterone system (e.g. patients with severe congestive heart failure or underlying renal
disease, including renal artery stenosis), treatment with other medicinal products that affect this system
has been associated with acute hypotension, azotaemia, oliguria or, rarely, acute renal failure. The
possibility of similar effects cannot be excluded with AIIRAs. As with any antihypertensive agent,
excessive blood pressure decrease in patients with ischaemic cardiopathy or ischaemic
cerebrovascular disease could result in a myocardial infarction or stroke.
Hypersensitivity reactions to hydrochlorothiazide may occur in patients with or without a history of
allergy or bronchial asthma, but are more likely in patients with such a history. Exacerbation or
activation of systemic lupus erythaematosus has been reported with the use of thiazide diuretics.
The antihypertensive effect of Candan Plus may be enhanced by other antihypertensives.
Choroidal effusion, acute myopia and secondary angle-closure glaucoma:
Sulfonamide or sulfonamide derivative drugs can cause an idiosyncratic reaction resulting in choroidal
effusion with visual field defect, transient myopia and acute angle-closure glaucoma. Symptoms
include acute onset of decreased visual acuity or ocular pain and typically occur within hours to weeks
of drug initiation. Untreated acute angle-closure glaucoma can lead to permanent vision loss. The
primary treatment is to discontinue drug intake as rapidly as possible. Prompt medical or surgical
treatments may need to be considered if the intraocular pressure remains uncontrolled. Risk factors for
developing acute angle-closure glaucoma may include a history of sulfonamide or penicillin allergy.
Candan Plus contains lactose. Patients with rare hereditary problems of galactose intolerance, the
Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product

Pregnancy
AIIRAs should not be initiated during pregnancy. Unless continued AIIRA therapy is considered
essential, patients planning pregnancy should be changed to alternative antihypertensive treatments
which have an established safety profile for use in pregnancy. When pregnancy is diagnosed,
treatment with AIIRAs should be stopped immediately, and, if appropriate, alternative therapy should
be started (see Contraindications and Pregnancy and lactation).

Dual RAAS blockade
The combination of aliskiren with ARBs or ACEIs is contracindicated in patients with diabetes mellitus
or renal impairment.
Dual blockade (e.g by adding an ACE-inhibitor to an angiotensin II receptor antagonist) should not be
used,especially in patients with kidney problems.
Compounds which have been investigated in clinical pharmacokinetic studies include warfarin, digoxin,
oral contraceptives (i.e. ethinylestradiol/levonorgestrel), glibenclamide and nifedipine. No
pharmacokinetic interactions of clinical significance were identified in these studies.
The potassium depleting effect of hydrochlorothiazide could be expected to be potentiated by other
medicinal products associated with potassium loss and hypokalaemia (e.g. other kaliuretic diuretics,
laxatives, amphotericin, carbenoxolone, penicillin G sodium, salicylic acid derivates, steroids, ACTH).
Concomitant use of Candan Plus and potassium-sparing diuretics, potassium supplements or salt
substitutes or other medicinal products that may increase serum potassium levels (e.g. heparin
sodium) may lead to increases in serum potassium. Monitoring of potassium should be undertaken as
appropriate (see Special warnings and precautions for use).
Diuretic-induced hypokalaemia and hypomagnesaemia predisposes to the potential cardiotoxic effects
of digitalis glycosides and antiarrhythmics. Periodic monitoring of serum potassium is recommended
when Candan Plus is administered with such medicinal products, and with the following medicinal
products that could induce torsades de pointes:
• Class Ia antiarrhythmics (e.g. quinidine, hydroquinidine, disopyramide)
• Class III antiarrhythmics (e.g. amiodarone, sotalol, dofetilide, ibutilide)
• Some antipsychotics (e.g. thioridazine, chlorpromazine, levomepromazine, trifluoperazine,
cyamemazine, sulpiride, sultopride, amisulpride, tiapride, pimozide, haloperidol, droperiodol)
• Others (e.g. bepridil, cisapride, diphemanil, erythromycin iv, halofantrin, ketanserin, mizolastin,
pentamidine, sparfloxacine, terfenadine, vincamine iv).
Reversible increases in serum lithium concentrations and toxicity have been reported during
concomitant administration of lithium with Angiotensin Converting Enzyme (ACE) inhibitors or
hydrochlorothiazide. A similar effect has also been reported with AIIRAs. Use of candesartan and
hydrochlorothiazide with lithium is not recommended. If the combination proves necessary, careful
monitoring of serum lithium levels is recommended.
When AIIRAs are administered simultaneously with non-steroidal anti-inflammatory drugs (NSAIDs)
(i.e. selective COX-2 inhibitors, acetylsalicylic acid (>3g/day) and non-selective NSAIDs), attenuation of
the antihypertensive effect may occur.

As with ACE inhibitors, concomitant use of AIIRAs and NSAIDs may lead to an increased risk of
worsening of renal function, including possible acute renal failure, and an increase in serum potassium,
especially in patients with poor pre-existing renal function. The combination should be administered
with caution, especially in the elderly. Patients should be adequately hydrated and consideration
should be given to monitoring renal function after initiation of concomitant therapy, and periodically
thereafter.
The diuretic, natriuretic and antihypertensive effect of hydrochlorothiazide is blunted by NSAIDs.

The absorption of hydrochlorothiazide is reduced by colestipol or cholestyramine.
The effect of nondepolarising skeletal muscle relaxants (e.g. tubocurarine) may be potentiated by
hydrochlorothiazide.
Thiazide diuretics may increase serum calcium levels due to decreased excretion. If calcium
supplements or Vitamin D must be prescribed, serum calcium levels should be monitored and the dose
adjusted accordingly.
The hyperglycaemic effect of beta-blockers and diazoxide may be enhanced by thiazides.
Anticholinergic agents (e.g. atropine, biperiden) may increase the bioavailability of thiazide-type
diuretics by decreasing gastrointestinal motility and stomach emptying rate.
Thiazide may increase the risk of adverse effects caused by amantadine.
Thiazides may reduce the renal excretion of cytotoxic medicinal products (e.g. cyclophosphamide,
methotrexate) and potentiate their myelosuppressive effects.
Postural hypotension may become aggravated by simultaneous intake of alcohol, barbiturates or
anaesthetics.
Treatment with a thiazide diuretic may impair glucose tolerance. Dose adjustment of antidiabetic
medicinal products, including insulin, may be required. Metformin should be used with caution because
of the risk of lactic acidosis induced by possible functional renal failure linked to hydrochlorothiazide.
Hydrochlorothiazide may cause the arterial response to pressor amines (e.g. adrenaline) to decrease
but not enough to exclude a pressor effect.
Hydrochlorothiazide may increase the risk of acute renal insufficiency especially with high doses of
iodinated contrast media.
Concomitant treatment with cyclosporine may increase the risk of hyperuricaemia and gout-type
complications.
Concomitant treatment with baclofen, amifostin, tricyclic antidepressants or neuroleptics may lead to
enhancement of the antihypertensive effect and may induce hypotension.

 

Pregnancy Category D
Use of drugs that act on the renin-angiotensin system during the second and third trimester of
pregnancy reduces fetal renal function and increase fetal and neonatal morbidity and death. Resulting
oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations.Potential
neonatal adverse effects include skull hypoplasia, anuria, hypotension,renal failure and death.When
pregnancy is detected,discontinue Candan Plus as soon as possible.

These adverse outcomes are usually associated with the use of these drugs in the second and third
trimester of pregnancy. Most epidemiologic studies examining fetal abnormalities after exposure to
antihypertensive use in the first trimester have not distinguished drugs affecting the renin- angiotensin
system from other antihypertensive agents.Appropriate management of maternal hypertension during
pregnancy is important to optimize outcomes for both mother and fetus
In the unusual case that there is no appropriate alternative to therapy with drugs affecting the reninangiotensin
system for a particular patient, apprise the mother of the potential risk to the fetus. Perform
serial ultrasound examination to assess the intra-amniotic environment. If oligohydramnios is observed,
discontinue Candan plus, unless it is considered lifesaving for the mother. Fetal testing may be
appropriate, based on the week of pregnancy. Patients and physicians should be aware, however that
oligohydramnios may not appear until after the fetus has sustained irreversible injury.Closely observe
infants with histories of in utero exposure to Candan plus for hypotension,oliguria and hyperkalemia.

Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE inhibitors
during the first trimester of pregnancy has not been conclusive; however, a small increase in risk
cannot be excluded. Whilst there is no controlled epidemiological data on the risk with AIIRAs, similar
risks may exist for this class of drugs. Unless continued AIIRA therapy is considered essential, patients
planning pregnancy should be changed to alternative antihypertensive treatments which have an
established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with AIIRAs
should be stopped immediately and, if appropriate, alternative therapy should be started.
Exposure to AIIRA therapy during the second and third trimesters is known to induce human
fetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal
toxicity (renal failure, hypotension, hyperkalaemia) (see Preclinical safety data).
Should exposure to AIIRAs have occurred from the second trimester of pregnancy, ultrasound check of
renal function and skull is recommended.
Infants whose mothers have taken AIIRAs should be closely observed for hypotension (see
contraindications and Special warnings and precautions for use).
Hydrochlorothiazide:
There is limited experience with hydrochlorothiazide during pregnancy, especially during the first
trimester. Animal studies are insufficient.
Hydrochlorothiazide crosses the placenta. Based on the pharmacological mechanism of action of
hydrochlorothiazide its use during the second and third trimesters may compromise foeto-placental
perfusion and may cause foetal and neonatal effects like icterus, disturbance of electrolyte balance and
thrombocytopenia.

Hydrochlorothiazide should not be used for gestational oedema, gestational hypertension or
preeclampsia due to the risk of decreased plasma volume and placental hypoperfusion, without a
beneficial effect on the course of the disease.
Hydrochlorothiazide should not be used for essential hypertension in pregnant women except in rare
situations where no other treatment could be used.
Lactation
It is not known whether candesartan is excreted in human milk, but candesartan has been shown to be
present in rat milk. Because of the potential for adverse effects on the nursing infant, a decision should
be made whether to discontinue nursing or discontinue Candan plus, taking into account the
importance of the drug to the mother.
Hydrochlorothiazide:
Hydrochlorothiazide is excreted in human milk in small amounts. Thiazides in high doses causing
intense diuresis can

No studies on the effects of candesartan on the ability to drive and use machines have been
performed. However, it should be taken into account that occasionally dizziness or weariness may
occur during treatment with Candan Plus.

In controlled clinical studies with candesartan cilexetil/hydrochlorothiazide adverse reactions were mild
and transient. Withdrawals from treatment due to adverse events were similar with candesartan
cilexetil/hydrochlorothiazide (2.3-3.3%) and placebo (2.7-4.3%).
In clinical trials with candesartan cilexetil/hydrochlorothiazide, adverse reactions were limited to those
that were reported previously with candesartan cilexetil and/or hydrochlorothiazide.
The table below presents adverse reactions with candesartan cilexetil from clinical trials and post
marketing experience. In a pooled analysis of clinical trial data of hypertensive patients, adverse
reactions with candesartan cilexetil were defined based on an incidence of adverse events with
candesartan cilexetil at least 1% higher than the incidence seen with placebo.
The frequencies used in the tables throughout section 4.8 are: very common (≥ 1/10), common (≥
1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (<
1/10,000) and not known (cannot be estimated from the available data).

Symptoms Based on pharmacological considerations, the main manifestation of an overdose of
candesartan cilexetil is likely to be symptomatic hypotension and dizziness. In individual case reports
of overdose (of up to 672 mg candesartan cilexetil) patient recovery was uneventful.
The main manifestation of an overdose of hydrochlorothiazide is acute loss of fluid and electrolytes.
Symptoms such as dizziness, hypotension, thirst, tachycardia, ventricular arrhythmias,
sedation/impairment of consciousness and muscle cramps can also be observed.
Management
No specific information is available on the treatment of overdose with Candan Plus. The following
measures are, however, suggested in case of overdose.
When indicated, induction of vomiting or gastric lavage should be considered. If symptomatic
hypotension should occur, symptomatic treatment should be instituted and vital signs monitored. The
patient should be placed supine with the legs elevated. If this is not sufficient, plasma volume should
be increased by infusion of isotonic saline solution. Serum electrolyte and acid balance should be
checked and corrected, if needed. Sympathomimetic medicinal products may be administered if the
above-mentioned measures are not sufficient.
Candesartan cannot be removed by haemodialysis. It is not known to what extent
hydrochlorothiazide is removed by haemodialysis.

Pharmaco-therapeutic group: Angiotensin II antagonists + diuretics, ATC code: C09DA06.
Angiotensin II is the primary vasoactive hormone of the renin-angiotensin-aldosterone system and
plays a role in the pathophysiology of hypertension and other cardiovascular disorders. It also has a
role in the pathogenesis of organ hypertrophy and end organ damage. The major physiological effects
of angiotensin II, such as vasoconstriction, aldosterone stimulation, regulation of salt and water
homeostasis and stimulation of cell growth, are mediated via the type 1 (AT1) receptor.
Candesartan cilexetil is a prodrug which is rapidly converted to the active drug, candesartan, by ester
hydrolysis during absorption from the gastrointestinal tract. Candesartan is an AIIRA, selective for AT1
receptors, with tight binding to and slow dissociation from the receptor. It has no agonist activity.
Candesartan does not influence ACE or other enzyme systems usually associated with the use of ACE
inhibitors. Since there is no effect on the degradation of kinins, or on the metabolism of other
substances, such as substance P, AIIRAs are unlikely to be associated with cough. In controlled
clinical trials comparing candesartan cilexetil with ACE inhibitors, the incidence of cough was lower in
patients receiving candesartan cilexetil. Candesartan does not bind to or block other hormone
receptors or ion channels known to be important in cardiovascular regulation. The antagonism of the
AT1 receptors results in dose related increases in plasma renin levels, angiotensin I and angiotensin II
levels, and a decrease in plasma aldosterone concentration.
The effects of candesartan cilexetil 8-16 mg (mean dose 12 mg) once daily on cardiovascular morbidity
and mortality were evaluated in a randomised clinical trial with 4,937 elderly patients (aged 70-89
years, 21% aged 80 or above) with mild to moderate hypertension followed for a mean of 3.7 years
(Study on COgnition and Prognosis in the Elderly). Patients received candesartan or placebo with
other antihypertensive treatment added as needed. The blood pressure was reduced from 166/90 to
145/80 mmHg in the candesartan group, and from 167/90 to 149/82 mmHg in the control group. There
was no statistically significant difference in the primary endpoint, major cardiovascular events
(cardiovascular mortality, non-fatal stroke and non-fatal myocardial infarction). There were 26.7 events
per 1000 patient-years in the candesartan group versus 30.0 events per 1000 patient-years in the
control group (relative risk 0.89, 95% CI 0.75 to 1.06, p=0.19).
Hydrochlorothiazide inhibits the active reabsorption of sodium, mainly in the distal kidney tubules, and
promotes the excretion of sodium, chloride and water. The renal excretion of potassium and
magnesium increases dose-dependently, while calcium is reabsorbed to a greater extent.
Hydrochlorothiazide decreases plasma volume and extracellular fluid and reduces cardiac output and
blood pressure. During long-term therapy, reduced peripheral resistance contributes to the blood
pressure reduction.
Large clinical studies have shown that long-term treatment with hydrochlorothiazide reduces the risk for
cardiovascular morbidity and mortality.
Candesartan and hydrochlorothiazide have additive antihypertensive effects.

In hypertensive patients, Candan Plus results in a dose-dependent and long-lasting reduction in arterial
blood pressure without reflex increase in heart rate. There is no indication of serious or exaggerated
first dose hypotension or rebound effect after cessation of treatment. After administration of a single
dose of Candan Plus, onset of the antihypertensive effect generally occurs within 2 hours. With
continuous treatment, most of the reduction in blood pressure is attained within four weeks and is
sustained during long-term treatment. Candan Plus once daily provides effective and smooth blood
pressure reduction over 24 hours, with little difference between maximum and trough effects during the
dosing interval. In a double-blind randomised study, Candan Plus 16 mg/12.5 mg once daily reduced
blood pressure significantly more, and controlled significantly more patients, than the combination
losartan/hydrochlorothiazide 50 mg/12.5 mg once daily. In double-blind, randomised studies, the
incidence of adverse events, especially cough, was lower during treatment with Candan Plus than
during treatment with combinations of ACE inhibitors and hydrochlorothiazide.
In two clinical studies (randomised, double-blind, placebo controlled, parallel group) including 275 and
1524 randomised patients, respectively, the candesartan cilexetil/hydrochlorothiazide combinations 32
mg/12.5 mg and 32 mg/25 mg resulted in blood pressure reductions of 22/15 mmHg and 21/14 mmHg,
respectively, and were significantly more effective than the respective monocomponents.
In a randomised, double-blind, parallel group clinical study including 1975 randomised patients not
optimally controlled on 32 mg candesartan cilexetil once daily, the addition of 12.5 mg or 25 mg
hydrochlorothiazide resulted in additional blood pressure reductions. The candesartan
cilexetil/hydrochlorothiazide combination 32 mg/25 mg was significantly more effective than the 32
mg/12.5 mg combination, and the overall mean blood pressure reductions were 16/10 mmHg and 13/9
mmHg, respectively.
Candesartan cilexetil/hydrochlorothiazide is similarly effective in patients irrespective of age and
gender.
Currently there are no data on the use of candesartan cilexetil/hydrochloro-thiazide in patients with
renal disease/nephropathy, reduced left ventricular function/congestive heart failure and post
myocardial infarction.

 

Concomitant administration of candesartan cilexetil and hydrochlorothiazide has no clinically significant
effect on the pharmacokinetics of either medicinal product.
Absorption and distribution Candesartan cilexetil
Following oral administration, candesartan cilexetil is converted to the active substance candesartan.
The absolute bioavailability of candesartan is approximately 40% after an oral solution of candesartan
cilexetil. The relative bioavailability of a tablet formulation of candesartan cilexetil compared with the
same oral solution is approximately 34% with very little variability. The mean peak serum concentration
(Cmax) is reached 3-4 hours following tablet intake. The candesartan serum concentrations increase
linearly with increasing doses in the therapeutic dose range. No gender related differences in the
pharmacokinetics of candesartan have been observed. The area under the serum concentration
versus time curve (AUC) of candesartan is not significantly affected by food.

Candesartan is highly bound to plasma protein (more than 99%). The apparent volume of distribution
of candesartan is 0.1 l/kg.
Hydrochlorothiazide
Hydrochlorothiazide is rapidly absorbed from the gastrointestinal tract with an absolute bioavailability of
approximately 70%. Concomitant intake of food increases the absorption by approximately 15%. The
bioavailability may decrease in patients with cardiac failure and pronounced oedema.
The plasma protein binding of hydrochlorothiazide is approximately 60%. The apparent volume of
distribution is approximately 0.8 l/kg.
Biotransformation and elimination Candesartan cilexetil
Candesartan is mainly eliminated unchanged via urine and bile and only to a minor extent eliminated
by hepatic metabolism (CYP2C9). Available interaction studies indicate no effect on CYP2C9 and
CYP3A4. Based on in vitro data, no interaction would be expected to occur in vivo with medicinal
products whose metabolism is dependent upon cytochrome P450 isoenzymes CYP1A2, CYP2A6,
CYP2C9, CYP2C19, CYP2D6, CYP2E1 or CYP3A4. The terminal half-life (t½) of candesartan is
approximately 9 hours. There is no accumulation following multiple doses. The half-life of candesartan
remains unchanged (approximately 9 h) after administration of candesartan cilexetil in combination with
hydrochlorothiazide. No additional accumulation of candesartan occurs after repeated doses of the
combination compared to monotherapy.
Total plasma clearance of candesartan is about 0.37 ml/min/kg, with a renal clearance of about 0.19
ml/min/kg. The renal elimination of candesartan is both by glomerular filtration and active tubular
secretion. Following an oral dose of 14C-labelled candesartan cilexetil, approximately 26% of the dose
is excreted in the urine as candesartan and 7% as an inactive metabolite while approximately 56% of
the dose is recovered in the faeces as candesartan and 10% as the inactive metabolite.

Hydrochlorothiazide
Hydrochlorothiazide is not metabolised and is excreted almost entirely as unchanged drug by
glomerular filtration and active tubular secretion. The terminal t½ of hydrochlorothiazide is
approximately 8 hours. Approximately 70% of an oral dose is eliminated in the urine within 48 hours.
The half-life of hydrochlorothiazide remains unchanged (approximately 8 h) after administration of
hydrochlorothiazide in combination with candesartan cilexetil. No additional accumulation of
hydrochlorothiazide occurs after repeated doses of the combination compared to monotherapy.
Pharmacokinetics in special populations Candesartan cilexetil
In elderly subjects (over 65 years), Cmax and AUC of candesartan are increased by approximately 50%
and 80%, respectively in comparison to young subjects. However, the blood pressure response and
the incidence of adverse events are similar after a given dose of CANDESARTAN Plus in young and
elderly patients (see Posology and method of administration).

In patients with mild to moderate renal impairment, Cmax and AUC of candesartan increased
during repeated dosing by approximately 50% and 70%, respectively, but the terminal t½ was
not altered, compared to patients with normal renal function. The corresponding changes in
patients with severe renal impairment were approximately 50% and 110%, respectively. The
terminal t½ of candesartan was approximately doubled in patients with severe renal impairment.
The pharmacokinetics in patients undergoing haemodialysis was similar to those in patients with
severe renal impairment.
In two studies, both including patients with mild to moderate hepatic impairment, there was an
increase in the mean AUC of candesartan of approximately 20% in one study and 80% in the
other study (see Posology and method of administration). There is no experience in patients
with severe hepatic impairment.
Hydrochlorothiazide
The terminal t½ of hydrochlorothiazide is prolonged in patients with renal impairment.

 

There were no qualitative new toxic findings with the combination compared to that observed for
each component. In preclinical safety studies candesartan itself had effects on the kidneys and
on red cell parameters at high doses in mice, rats, dogs and monkeys. Candesartan caused a
reduction of red blood cell parameters (erythrocytes, haemoglobin, haematocrit). Effects on the
kidneys (such as regeneration, dilatation and basophilia in tubules; increased plasma
concentrations of urea and creatinine) were induced by candesartan which could be secondary
to the hypotensive effect leading to alterations of renal perfusion. Addition of
hydrochlorothiazide potentiates the nephrotoxicity of candesartan. Furthermore, candesartan
induced hyperplasia/hypertrophy of the juxtaglomerular cells. These changes were considered
to be caused by the pharmacological action of candesartan and to be of little clinical relevance.
Foetotoxicity has been observed in late pregnancy with candesartan. The addition of
hydrochlorothiazide did not significantly affect the outcome of foetal development studies in rats,
mice or rabbits (see Pregnancy and lactation).
Candesartan and hydrochlorothiazide both show genotoxic activity at very high
concentrations/doses. Data from in vitro and in vivo genotoxicity testing indicate that
candesartan and hydrochlorothiazide are unlikely to exert any mutagenic or clastogenic activity
under conditions of clinical use.
There was no evidence that either compound is carcinogenic.

Lactose Monohydrate

Maize Starch
Hydroxypropyl cellulose
Polyethylene glycol 8000
Calcium carboxymethyl cellulose
Red Iron Oxide
Yellow Iron Oxide
Magnesium stearate

Not applicable.

Two years

Store below 30˚C.

ALU/PVC /PVDC blisters of 30 Tablets.

No special requirements.